One or more embodiments of the present invention comprise pharmaceutical compositions comprising one or more fluoroquinolones, such as ciprofloxacin. One or more embodiments of the present invention comprise powders comprising the betaine form of one or more fluoroquinolones, such as ciprofloxacin betaine. One or more embodiments of the present invention comprise methods of making, using and/or administering such pharmaceutical compositions, dosage forms thereof and devices, systems and methods for the pulmonary delivery of such compositions.
This invention relates to compositions and methods for treating bacterial infections, and has particular reference to the treatment of cystic fibrosis (CF), non-CF bronchiectasis, and acute exacerbations in chronic obstructive pulmonary disease.
Cystic fibrosis is the most common life-shortening genetic disease in the United States and Northern Europe, affecting approximately 30,000 individuals in the United States and a similar number of individuals in Western Europe. The genetic defect in this autosomal recessive disease is a mutation in the CF transmembrane conductance regulator (CFTR) gene, which codes for a chloride-channel protein. Persons with CF typically suffer from chronic endobronchial infections, sinusitis, and malabsorption due to pancreatic insufficiency, increased salt loss in sweat, obstructive hepatobiliary disease, and reduced fertility Respiratory disease is a major cause of morbidity and accounts for 90% of mortality in persons with CF. Lung function (measured as forced expiratory volume at 1 second (FEV1% predicted) is a significant predictor of survival in CF. Two-year survival for a given population of persons with CF is reduced 2-fold with each 10% reduction in FEV1% predicted, and persons with FEV1 below 30% of predicted have a 2-year survival below 50% (Kerem, E. et al., “Prediction of Mortality in Patients with Cystic Fibrosis,” N Engl J Med 326:1187-1191 (1992)). Rates of lung function loss vary both between individuals and over time for a given individual. Retrospective longitudinal analyses show rates of decline ranging from less than 2% of FEV1% predicted per year to greater than 9% FEV1% predicted per year, with overall rate of decline strongly associated with age of death.
CF patients suffer from thickened mucus believed to be caused by perturbed epithelial ion transport that impairs lung host defenses, resulting in increased susceptibility to early endobronchial infections with Staphylococcus aureus, Haemophilus influenzae, and Pseudomonas aeruginosa. By adolescence, a majority of persons with CF have P. aeruginosa present in their sputum. Chronic endobronchial infections, particularly with P. aeruginosa, provoke a persistent inflammatory response in the airway that accelerates progressive obstructive disease characterized by diffuse bronchiectasis; Winnie, G. B. et al., “Respiratory Tract Colonization with Pseudomonas aeruginosa in Cystic Fibrosis: Correlations Between AxAi-Pseudomonas aeruginosa Antibody Levels And Pulmonary Function,” Pediatr Pulmonol 10:92-100 (1991). A link between acquisition of chronic endobronchial P. aeruginosa infection, lung inflammation, loss of lung function, and ultimate death is suggested by significantly decreased survival associated with chronic P. aeruginosa infection (Henry, R. L. et al., “Mucoid Pseudomonas aeruginosa is a Marker of Poor Survival in Cystic Fibrosis,” Pediatr Pulmonol 12(3):158-61 (1992)), and by the significant association of early acquisition of chronic P. aeruginosa infection and childhood mortality (Demko, Calif. et al., “Gender Differences in Cystic Fibrosis: Pseudomonas aeruginosa Infection,” J Clin Epidemiol 48:1041-1049 (1995)).
Various therapies have been attempted to treat P. aeruginosa in CF patients. These therapies aim to either suppress bacterial loads in the lung or suppress resulting inflammation. Such therapies have been shown to reduce rates of lung function decline in infected patients, but have shortcomings.
Historically, the standard therapy for treatment of P. aeruginosa endobronchial infections was 14 to 21 days of parenteral antipseudomonal antibiotics, typically including an aminoglycoside. However, the inability of these agents to pass efficiently from the bloodstream into the lung tissue and airway secretions resulted in sub-therapeutic concentrations at the target site. As a result, repeated exposure to parenteral aminoglycosides led to development of resistant isolates which were associated with production of more mucus and a variety of virulence factors. To obtain adequate drug concentrations at the site of infection with parenteral administration, serum levels approaching those associated with nephro-, vestibule-, and oto-toxicity were required (“American Academy of Otolaryngology. Guide for the evaluation of hearing handicap,” JAMA 241(19):2055-9 (1979); Brummett, R. E., “Drug-induced ototoxicity,” Drugs 19:412-28 (1980)).
Inhalation administration of antibiotics, such as aminoglycosides has offered an attractive alternative, delivering high concentrations of antibiotic directly to the site of infection in the endobronchial space while minimizing systemic bioavailability.
For example, TOBI®, which comprises the aminoglycoside Tobramycin, is approved for inhalation therapy for the treatment of endobronchial infections in CF patients [NDA 50-753]. Since its approval, TOBI® (Novartis, Basel, Switzerland), has become the standard of care in CF patients chronically colonized with P. aeruginosa. Patients receive a 300 mg nominal dose, administered with a standard jet nebulizer twice daily. Patients receive a 28 day “on” therapy followed by a 28 day “off” period, to reduce the potential for development of resistant bacterial strains. However, of the 300 mg dose, only approximately 10% or 30 mg is delivered to the lung. Clinical studies with TOBI® have shown that inhaled tobramycin has dramatically reduced systemic side-effects. The aerosol administration of a 5 ml dose of a formulation containing 300 mg of tobramycin in quarter normal saline for the suppression of P. aeruginosa in the endobronchial space of a patient is disclosed in U.S. Pat. No. 5,508,269, the disclosure of which is incorporated herein in its entirety by this reference.
There are limitations on the use of tobramycin in CF patients. Systemic tobramycin given by IV injection can have serious adverse effects including renal and ototoxicity. Nebulized liquids may possess issues related to the preparation and administration thereof, as well as the development of increased resistance (i.e., increase in minimal inhibitory concentration value, MIC) for P. aeruginosa during treatment. The treatment regimen of one month on and one month off therapy has to be maintained to avoid the development of resistance allowing the susceptible pathogens to repopulate, despite the risk of deterioration in pulmonary function. Long-term impact of inhaled aminoglycosides on kidney function is not well understood. The 5 mL dose requires about 15-20 min to administer with additional time for set-up and nebulizer cleaning. Nebulization may have other disadvantages, such as cost, efficiency and reproducibility, risk of bacterial contamination, and the lack of portability (need for bulky compressors or gas cylinders and power sources).
In addition to inhaled antibiotics such as the commercially available TOBI product, a variety of other chronic therapies are routinely prescribed to reduce the destructive cycles of obstruction, infection, and inflammation in the CF lung. Aggressive airway clearance therapy, inhaled bronchodilators, and mucolytics such as recombinant human dornase alpha are all prescribed chronically, creating a potential for significant treatment burden for persons with CF. Many CF patients spend more than four hours daily receiving therapy. Not surprisingly, it has been shown that adherence to treatment therapies is a significant problem for CF patients and that lack of compliance can vary by specific treatment. In view of the extended treatment times, any regimens that can significantly reduce the time of administration, and the convenience associated with administration (e.g., device portability and ease of use) are advantageous, potentially improving patient compliance and outcomes. As well, the development of alternative inhaled antibiotic formulations which can be administered in the TOBI off-period may provide a treatment alternative which does not require repopulation of susceptible pathogens and loss in pulmonary function.
Ciprofloxacin is a synthetic, fluorinated carboxyquinolone with a broad spectrum of activity. Ciprofloxacin selectively inhibits bacterial deoxyribonucleic acid (DNA) synthesis by acting on DNA gyrase and topoisomerase IV. These essential enzymes control DNA topology and assist in DNA replication, repair, and transcription. Ciprofloxacin has been shown to have good in-vitro bactericidal activitiy against a number of pathogens that cause respiratory infections, including Mycobacterium tuberculosis, Mycobacterium avium-M. intracellulare, Bacillus anthracis, Hemophilus influenzae, Neisseria meningitidis, and Pseudomonas aeruginosa. Ciprofloxacin is currently regarded as one of the most if not the most active fluoroquinolone against P. aeruginosa, and is highly bactericidal. Oral and intravenous forms of ciprofloxacin have been used clinically to treat respiratory tract infections.
Despite the success with ciprofloxacin, there are some factors which limit the drug's clinical utility for treating lung infections, such as its poor solubility at physiological pH, bitter taste in solution, and rapid renal clearance. For example, in order to administer a 500 mg intravenous dose, the drug must first be diluted to <2 mg/ml and infused slowly to avoid precipitation at the site of injection. Ciprofloxacin administered intravenously or orally also has unfavorable pharmacokinetic profiles in the lower respiratory tract, including a relatively short elimination half-life of 1.0 to 1.6 hr, and a low area under the concentration-time curve of 43 to 113 mg h/L.
Inhalation of ciprofloxacin by patients in need thereof, such as CF patients, COPD patients and anthraz patients, would be expected to result in high bactericidal concentrations in the airways. Even sub-inhibitory concentrations of ciprofloxacin affect the virulence of P. aeruginosa (quorum sensing), and potentially reduce the incidence of chronic airway infections in CF patients. Reducing the airway bacterial load and potentially slowing re-infection may translate into improved lung function and contribute to an improved long-term prognosis. Moreover, inhalation of ciprofloxacin may overcome the potential for renal insufficiency noted following treatment with aminoglycosides.
However, effective pulmonary delivery of ciprofloxacin has proven to be difficult. A challenge associated with the delivery of antiinfectives such as ciprofloxacin to the lungs is the potential for rapid clearance of the drug via: (a) mucociliary clearance from the airways; (b) absorption of drug into the systemic circulation; (c) clearance via pulmonary macrophages. Following intratracheal administration, soluble ciprofloxacin hydrochloride is rapidly absorbed from the lungs into the systemic circulation with a half-life of just 0.2 hr (Wong J P, Cherwonogroszky J W, DiNinno V L et al: Liposome-encapsulated ciprofloxacin for the prevention and treatment of infectious diseases caused by intracellular pathogens. In: “Liposomes in Biomedical Applications” (Florence A T, Gregoriadis G, eds) Harwood Academic Press, Amsterdam, 1995, p 105-120). This is too short to achieve effective treatment of endobronchial P. aeruginosa infections, and presents a significant constraint for formulation development.
In order to overcome the rapid clearance of ciprofloxacin hydrochloride from the lungs, researchers have explored encapsulation in controlled release carriers, such as liposomes. For example Wong and coworkers showed significant increases in lung residence time with liposomal ciprofloxacin, which translated into effective treatment of Francicella tularensis infections in a rodent model. Limitations for liposomal delivery of ciprofloxacin via nebulization include: (a) extended administration times due to low drug loadings and limits on dispersion concentrations acceptable for nebulization (viscosity constraint); (b) limited control of the release kinetics. In the Wong study, a standard jet nebulizer was used. Such nebulizers typically provide a flow rate of 0.1 to 0.2 ml/min. At the drug content of 10-40 μg/ml, the flow rate was 1 to 8 μg/min. Assuming about 10% delivery efficiency, only 0.1 to 0.8 μg/min would be delivered to the lungs. Hence, delivery of lung doses greater than 10 mg is not practical using this model.
The utilization of polymeric carriers as a means to prolong lung residence time of ciprofloxacin hydrochloride has not been advanced into clinical practice. Concerns remain with respect to the slow clearance of polymeric carriers from the lungs.
At pH values below pK1 (6.0) and above pK2 (8.8), ciprofloxacin has a net charge and is highly soluble. In the pH range between 6.0 and 8.8, the compound is zwitterionic, and is practically insoluble (solubility at pH 7 is 60 μg/ml). Studies have demonstrated that the zwitterionic form, ciprofloxacin betaine, has an extended residence time in the lungs (Endermann R, Labischinski H, Ladel C et al: Treatment of bacterial diseases of the respiratory organs. US Patent Appl US 2004/0254194 A1). However, Endermann et al do not teach the administration of ciprofloxacin betaine in a form that is easily, effectively, and reproducibly deliverable to a patient.
In addition, one of the key challenges faced in the pulmonary delivery of antiinfectives is the magnitude of the therapeutic lung doses (>10 mg) that are required. Asthma therapeutics (e.g., bronchodilators and corticosteroids) dominate the aerosol delivery market. As shown in FIG. 1, asthma drugs are highly potent with delivered lung doses of less than about 100 micrograms (μg.) See also Weers J, Clark A, Challoner P: High dose inhaled powder delivery: challenges and techniques. In: “Respiratory Drug Delivery IX” (R N Dalby, P R Byron, J Peart, J D Suman, S J Farr, Eds) Davis Healthcare Intl Publishing, River Grove, Ill., 2004, pp 281-288.
Thus, existing therapies suffer from several deficiencies. In view of the known systems for administering antibiotic aerosols, there remains a need for high efficiency and more convenient systems. One or more embodiments of the present invention satisfy one or more of these needs.